Modified Project Summary/Abstract Section This project is the R00 phase of a K99/R00 award to be conducted at the Neuroscience Institute at Georgia State University. The candidate will assume a tenure-track assistant professor position, set up a new lab, and, armed with new skills and insights from the k99 phase, continue the originally proposed experiments aimed at understanding the interaction of frontal and sensory cortical circuits supporting perceptual novelty processing. Sensory stimuli are naturally perceived within a spatiotemporal and behavioral context, wherein novel events are processed and repetitive elements ignored. Novelty detection is thus cognitive as well as perceptual and is critical for daily function and survival. Studies using ?oddball? stimuli demonstrate that psychiatric disorders, including schizophrenia (SZ), involve abnormal sensorineuronal processing of novelty which predicts deficits in cognition and everyday functioning. In his PhD, the candidate characterized the multivariate complexity and heritability of oddball EEG responses to show how they could help build a biological taxonomy of psychosis. Yet a mechanistic understanding of how brain circuits process context, and the pathophysiology underlying patient deficits, is unattainable with human studies alone. As a postdoc, the candidate mastered two-photon calcium imaging (2P-Ca++) and chemicogenetics to develop a mouse model of novelty detection in visual cortical circuits (V1), showing a key role for somatostatin interneurons, a pathophysiologically relevant cell type in SZ. While context processing involves ongoing adaptations within sensory cortex, it also requires information about the past and behavioral goals, which may implicate larger brain networks involving prefrontal cortex (PFC). AIM1 expands the candidates work in V1 to study the mechanisms and nature of PFC?s top-down influence. Experiments will test how direct axonal inputs from PFC actively modify the multicellular circuit dynamics in V1 during in oddball paradigms. In the K99 phase, the candidate learned state of the art holographic technique using spatial light modulators (SLM) and Electrotunable lenses (ETLs) to enable the observation and manipulation of these circuits. Results demonstrated that novel vs standard events are represented by a separate sets of neurons in V1, and the only overall magnitudes of these responses are modulated by PFC inputs. As originally planned, the candidate will follow-up on these observations in the R00 phase using optogenetic manipulation of specific circuit elements (e.g. PFC inputs to interneurons) to provide mechanistic insight into these ?ensemble? dynamics. Patient oddball studies highlight deficits in both passive (automatic) and active (attentional) aspects of novelty processing, which may involve non-overlapping neural pathophysiology. In AIM2, the candidate will uncover the behavioral relevance of this PFC-V1 circuit. In the K99 phase, the candidate learned to design behavioral training protocols in head-fixed mice, eliciting responses to novelty in a dynamic oddball paradigm. Building on findings from in AIM1, the candidate will differentiate attentive from pre-attentive circuit functions and establish when and how context is encoded and used to guide behavior.